Tuberculosis
journal homepage: http://intl.elsevierhealth.com/journals/tube
REVIEW
a r t i c l e i n f o
s u m m a r y
Article history:
Received 31 March 2012
Received in revised form
22 May 2012
Accepted 29 May 2012
Children are among the subjects most frequently affected by tuberculous meningitis (TBM) due to their
relative inability to contain primary Mycobacterium tuberculosis infection in the lung. TBM is a devastating disease with about 30% mortality among the most severe cases; moreover, 50% of survivors have
neurological sequelae despite an apparently adequate administration of antibiotics. Early diagnosis and
prompt treatment are crucial for reducing the risk of a poor outcome. However, especially in children, the
best and most rapid way to conrm the diagnosis is controversial; the optimal choice, dose, and treatment duration of anti-tuberculosis drugs are not precisely dened, and the actual importance of
adjunctive therapies with steroids and neurosurgery has not been adequately demonstrated. This review
is an effort to discuss present knowledge of the diagnosis and treatment of pediatric TBM in order to offer
the best solution to address this dramatic disease. In conclusion, we stress that new studies in children
are urgently needed because data in the early years of life are more debatable than those collected in
adults. In the meantime, when treating a child with suspected TBM, the most aggressive attitude to
diagnosis and therapy is necessary, because TBM is a devastating disease.
2012 Elsevier Ltd. All rights reserved.
Keywords:
Children
Meningitis
Mycobacterium tuberculosis
Tuberculosis
Tuberculous meningitis
1. Introduction
Tuberculous meningitis (TBM) occurs mainly in developing
countries where tuberculosis (TB) is more common and the wider
incidence of the human immunodeciency virus (HIV) favors the
onset of a great number of cases. However, TBM is also encountered
in industrialized countries, particularly in recent years, as a consequence of the large immigration of infected people1 and the
frequent use of biological agents that favor TB development.2,3
Children are among the subjects who most frequently suffer from
TBM due to their relative inability to contain primary Mycobacterium tuberculosis infection in the lung.1,3 TBM is a devastating
disease with about 30% mortality in the most severe forms;
moreover, 50% of survivors have neurological sequelae despite
apparently adequate administration of antibiotics.4,5 Early diagnosis and prompt treatment are crucial for reducing the risk of
a negative evolution. However, especially in children, the best and
most rapid way to diagnose the disease is controversial; the
optimal choice, dose, and treatment duration of anti-tuberculosis
drugs are not precisely dened, and the actual importance of
adjunctive therapies with steroids and neurosurgery have not been
adequately demonstrated. Consequently, the approach to pediatric
TBM is frequently inadequate. This review is aimed at discussing
* Corresponding author. Tel.: 39 02 55032203; fax: 39 02 50320206.
E-mail address: nicola.principi@unimi.it (N. Principi).
1472-9792/$ e see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tube.2012.05.011
378
Maximum category
score 6
4
2
1
1
1
Maximum category
score 4
1
1
1
1
1
Maximum category
score 6
1
2
2
1
2
Maximum category
score 4
2/4
2
4
CNS, central nervous system; CT, computed tomography; MR, magnetic resonance;
NAAT, nucleic acid amplication test; TB, tuberculosis.
From Marais et al.,8 modied.
379
3. Treatment
Treatment of TBM is based on three different components:
administration of anti-infective drugs active against M. tuberculosis,
modulation of the destructive elements of the immune response,
and management of increased intracranial pressure.
380
Table 2
Main guidelines for the treatment of tuberculous meningitis in infants and children.
British Infection Society
Isoniazid 10e20 mg/kg/24 h (max 500 mg) orally for 12 months
Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 12 months
Pyrazinamide 30e35 mg/kg/24 h (max 2 g) orally for 2 months
Ethambutol 15e20 mg/kg/24 h (max 1 g) orally for 2 months
Prednisolone 4 mg/kg/24 h orally for 4 weeks, followed by a
reducing course over 4 weeks
American Thoracic Society, CDC, and Infectious Diseases Society of America
Isoniazid 10e15 mg/kg/24 h (max 300 mg) orally for 9e12 months
Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 9e12 months
Pyrazinamide 15e30 mg/kg/24 h (max 2 g) orally for 2 months
Ethambutol 15e20 mg/kg/24 h (max 1 g) orally for 2 months
Dexamethasone 8 mg/day/24 h orally for children weighing less than 25 kg
and 12 mg/day for children weighing 25 kg or more for 3 weeks,
followed by a reducing course over 3 weeks
World Health Organization
Isoniazid 10e15 mg/kg/24 h (max 300 mg) orally for 6 months
Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 6 months
Pyrazinamide 15e30 mg/kg/24 h (max 2 g) orally for 2 months
Streptomycin 20e40 mg/kg (max 1 g) i.m. or i.v. for 2 months
Prednisone 2 mg/kg/24 h orally for 4 weeks, followed by a
reducing course over 1e2 weeks
Table 3
Recommended daily dosages of second-line anti-tuberculous drugs for treatment of
tuberculous meningitis in infants and children.
Drug
Dosage
Ethionamide
Cycloserine
Steptomycin
Para-amino-salicylic acid
Capreomycin
Amikacin and Kanamycin
Ooxacin
Levooxacin
Moxioxacin
Ciprooxacin
381
Funding:
This study was supported by a grant from the Italian
Ministry of Health (Bando Giovani Ricercatori 2007).
Competing interests:
to declare.
Ethical approval:
This review was approved by the Ethical
Committee of Fondazione IRCCS Ca Granda Ospedale Maggiore
Policlinico, Milan, Italy and all the papers included in this review
have been approved by local Ethical Committees.
References
1. Bidstrup C, Andersen PH, Skinhj P, Andersen AB. Tuberculous meningitis in
a country with a low incidence of tuberculosis: still a serious disease and
a diagnostic challenge. Scand J Infect Dis 2002;34:811e4.
2. Keane J. TNF-blocking agents and tuberculosis: new drugs illuminate an old
topic. Rheumatology (Oxford) 2005;44:714e20.
3. Lewinsohn DA, Gennaro ML, Scholvinck L, Lewinsohn DM. Tuberculosis
immunology in children: diagnostic and therapeutic challenges and opportunities. Int J Tuberc Lung Dis 2004;8:658e74.
4. Farinha NJ, Razali KA, Holzel H, Morgan G, Novelli VM. Tuberculosis of the
central nervous system in children: a 20-year survey. J Infect 2000;41:61e8.
5. Saitoh A, Pong A, Waecker Jr NJ, Leake JA, Nespeca MP, Bradley JS. Prediction of
neurologic sequelae in childhood tuberculous meningitis: a review of 20 cases
and proposal of a novel scoring system. Pediatr Infect Dis J 2005;24:207e12.
6. Khemiri M, Bagais A, Ben Becher S, Bousnina S, Bayoudh F, Mehrezi A, et al.
Tuberculous meningitis in Bacille Calmette-Guerin-vaccinated children: clinical
spectrum and outcome. J Child Neurol 2011 [Epub Dec 21].
7. Starke JR. Tuberculosis of the central nervous system in children. Semin Pediatr
Neurol 1999;6:318e31.
8. Marais S, Thwaites G, Schoeman JF, Trk ME, Misra UK, Prasad K, et al.
Tuberculous meningitis: a uniform case denition for use in clinical research.
Lancet Infect Dis 2010;10:803e12.
9. Kumar R, Singh SN, Kohli N. A diagnostic rule for tuberculous meningitis. Arch
Dis Child 1999;81:221e4.
10. Tuon FF, Higashino HR, Lopes MI, Litvoc MN, Atomiya AN, Antonangelo L, et al.
Adenosine deaminase andtuberculous meningitis e a systematic review with
meta-analysis. Scand J Infect Dis 2010;42:98e207.
11. Corral I, Quereda C, Navas E, Martn-Dvila P, Prez-Elas MJ, Casado JL, et al.
Adenosine deaminase activity in cerebrospinal uid of HIV-infected patients:
382
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39. Pai M, Flores LL, Pai N, Hubbard A, Riley LW, Colford Jr JM. Diagnostic accuracy
of nucleic acid amplication tests for tuberculous meningitis: a systematic
review and meta-analysis. Lancet Infect Dis 2003;3:633e43.
40. Jonas V, Alden MJ, Curry JI, Kamisango K, Knott CA, Lankford R, et al. Detection
and identication of Mycobacterium tuberculosis directly from sputum sediments by amplication of rRNA. J Clin Microbiol 1993;31:2410e6.
41. Brisson-Nol A, Gicquel B, Lecossier D, Lvy-Frbault V, Nassif X, Hance AJ.
Rapid diagnosis of tuberculosis by amplication of Mycobacterial DNA in
clinical samples. Lancet 1989;2:1069e71.
42. Kusum S, Aman S, Pallab R, Kumar SS, Manish M, Sudesh P, et al. Multiplex PCR
for rapid diagnosis of tuberculous meningitis. J Neurol 2011;258:1781e7.
43. Helb D, Jones M, Story E, Boehme C, Wallace E, Ho K, et al. Rapid detection of
Mycobacterium tuberculosis and rifampin resistance by use of on-demand,
near-patient technology. J Clin Microbiol 2010;48:229e37.
44. Takahashi T, Tamura M, Asami Y, Kitamura E, Saito K, Suzuki T, et al. Novel
wide-range quantitative nested real-time PCR assay for Mycobacterium tuberculosis DNA: clinical application for diagnosis of tuberculous meningitis. J Clin
Microbiol 2008;46:1698e707.
45. Centers for Disease Control. Treatment of tuberculosis. MMWR Recomm Rep
2003;52:1e77.
46. Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J. British
Infection Society guidelines for the diagnosis and treatment of tuberculosis of
the central nervous system in adults and children. J Infect 2009;59:167e87.
47. Donald PR. The chemotherapy of tuberculous meningitis in children and adults.
Tuberculosis 2010;90:375e92.
48. van Loenhout-Rooyackers JH, Keyser A, Laheij RJF, Verbeek ALM, van der
Meer JWM. Tuberculous meningitis: is a 6-month treatment regimen sufcient? Int J Tuberc Lung Dis 2001;5:1028e35.
49. Woodeld J, Argent A. Evidence behind the WHO guidelines: hospital care for
children: what is the most appropriate anti-microbial treatment for tuberculous meningitis. J Trop Pediatr 2008;54:2210e24.
50. World Health Organization Stop TB Department. Treatment of tuberculosis
guidelines for national programmes. 3rd ed. Geneva: World Health Organization; 2003.
51. Donald PR, Seifart HI. Cerebrospinal uid concentrations of ethionamide in
children with tuberculous meningitis. J Pediatr 1989;115:483e6.
52. Kernbaum S. Treatment of tuberculous meningitis. J Pediatr 1975;87:837e8.
53. Donald PR, Parkin DP, Seifart HI, Schaaf HS, van Helden PD, Werely CJ, et al. The
inuence of dose and N-acetyltransferase genotype and phenotype on the
pharmacokinetics and pharmacodynamics of isoniazid. Eur J Clin Pharmacol
2007;63:633e9.
54. Donald PR, Gent WL, Seifart HI, Lamprecht JH, Parkin DP. Cerebrospinal uid
isoniazid concentrations in children with tuberculous meningitis: the inuence
of dosage and acetylation status. Pediatrics 1992;89:247e50.
55. Ellard GA, Humphries MJ, Allen BW. Cerebrospinal uid drug concentrations
and the treatment of tuberculous meningitis. Am Rev Respir Dis
1993;148:650e5.
56. Peloquin CA, Namdar R, Singleton MD, Nix DE. Pharmacokinetics of rifampin
under fasting conditions, with food and with antacids. Chest 1999;115:12e8.
57. Boman G, Ringberger VA. Binding of rifampicin by human plasma proteins. Eur
J Clin Pharmacol 1974;7:369e73.
58. Schaaf HS, Willemse M, Cilliers K, Labadarios D, Maritz JS, Hussey GD, et al.
Rifampin pharmacokinetics in children, with and without human immunodeciency virus infection, hospitalized for the management of severe forms of
tuberculosis. BMC Med 2009;22:19.
59. Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of
drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis
1980;121:939e49.
60. Botha FJH, Sirgel FA, Parkin DP, Van de Wal BW, Donald PR, Mitchison DA. Early
bactericidal activity of ethambutol, pyrazinamide and the xed combination of
isoniazid, rifampicin and pyrazinamide (Rifater) in patients with pulmonary
tuberculosis. South Afr Med J 1996;86:151e8.
61. East African/British Medical Research Councils. Controlled clinical trial of shortcourse (6-month) regimens of chemotherapy for treatment of pulmonary
tuberculosis. Lancet 1972;1:1079e85.
62. Donald PR, Seifart HI. Cerebrospinal uid pyrazinamide concentrations in
children with tuberculosis meningitis. Pediatr Infect Dis J 1988;7:469e71.
63. Seddon JA, Visser DH, Bartens M, Jordaan AM, Victor TC, van Furth AM, et al.
Impact of drug resistance on clinical outcome in children with tuberculous
meningitis. Pediatr Infect Dis J 2012 [Epub Mar 9].
64. Thwaites GE, Lan NT, Dung NH, Quy HT, Oanh DT, Thoa NT, et al. Effect of
antituberculosis drug resistance on response to treatment and outcome in
adults with tuberculous meningitis. J Infect Dis 2005;192:79e88.
65. Tho DQ, Trk ME, Yen NT, Bang ND, Lan NT, Kiet VS, et al. Inuence of antituberculosis drug resistance and Mycobacterium tuberculosis lineage on
outcome in HIV-associated tuberculous meningitis. Antimicrob Agents Chemother 2012;56:3074e9.
66. Koedel U, Klein M, Pster HW. New understandings on the pathophysiology of
bacterial meningitis. Curr Opin Infect Dis 2010;23:217e23.
67. Lammie GA, Hewlett RH, Schoeman JF. Donald PRTuberculous cerebrovascular
disease: a review. J Infect 2009;59:156e66.
68. Prasad K, Singh MB. Corticosteroids for managing tuberculos meningitis.
Cochrane Database Syst Rev 2008;1:CD002244.
69. Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA. Dexamethasone adjunctive
treatment for tuberculous meningitis. Pediatr Infect Dis J 1991;10:179e83.
383